CGRP Receptor Antagonists

ABSTRACT

The disclosures herein relate to novel compounds of formula 
     
       
         
         
             
             
         
       
     
     wherein R 1 , R 2  and R 3  are as defined herein, and their use in treating, preventing, ameliorating, controlling or reducing cerebrovascular or vascular disorders associated with CGRP receptor function.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a divisional of U.S. patent application Ser. No.15/336,880, filed on Oct. 28, 2016, which claims the benefit of GreatBritain Patent Application No. 1519195.0, filed Oct. 30, 2015, each ofwhich is incorporated in its entirety by reference herein.

TECHNICAL FIELD

This application relates to novel compounds and their use as CGRPreceptor antagonists. Compounds described herein may be useful in thetreatment or prevention of cerebrovascular or vascular disorders such asmigraine. The application is also directed to pharmaceuticalcompositions comprising these compounds and the manufacture and use ofthese compounds and compositions in the prevention or treatment of suchcerebrovascular or vascular disorders.

BACKGROUND OF THE INVENTION

Migraine is a highly disabling neurovascular disorder characterized byattacks of moderate to severe headache that are often associated withnausea, vomiting, photophobia, and phonophobia. The attacks can lastfrom 4 to 72 h, and the average attack frequency is 1 or 2 per month.About 20-30% of migraine patients experience transient focal neurologicsymptoms known as aura, which are usually visual and can precede oraccompany the headache. Migraine afflicts about 11% of adults worldwideand results in a significant socioeconomic burden, in terms of bothquality of life and lost productivity.

Whilst the pathomechanism of migraine is still unclear, one of theleading hypotheses is based on activation of the trigeminovascularsystem (TS). Several neuropeptides participate in this activation,calcitonin gene-related peptide (CGRP) playing a crucial role amongthem. CGRP exerts various biological effects through the peripheral andcentral nervous system (CNS). The functional CGRP-receptor (CGRP-R)complex has been well characterized, and novel therapeutic approachestarget CGRP itself and its receptors. This invention relates to thedevelopment of CGRP receptor antagonists (CGRP-RA).

CGRP, a 37-amino acid neuropeptide derived from the gene encodingcalcitonin, is formed from the alternative splicing of thecalcitonin/CGRP gene located on chromosome 11. In humans, CGRP has twoisoforms: α- and β-CGRP. The β-isoform differs from the α-isoform in theamino acids located at positions 3, 22 and 25. The chemical structure ofCGRP involves a disulphide bridge between residues 2 and 7 and anamidated C-terminus. The cyclic cysteine2-cysteine7 motif has a basicrole in receptor activation. In the human trigeminal ganglia (TRIG),CGRP-immunoreactive neurons account for up to 50% of all neurons. It hasbeen demonstrated through an in situ hybridization technique that 40% ofall nerve cell bodies contain CGRP mRNA and CGRP. Double immunostaininghas shown that in the human TRIG CGRP is co-localized with nitric oxidesynthase, substance P (SP), pituitary adenylate cyclase activatingpeptide (PACAP) and nociceptin, which may play a role in thepathomechanism of migraine.

The functional CGRP-R consists of three proteins: i) Calcitonin ReceptorLike Receptor (known as CRLR, CALCRL or CLR) is a seven-transmembranespanning protein, which forms the ligand binding site with; ii) RAMP1,determining the specificity of the receptor; and iii) the CGRP-Rcomponent protein (RCP) couples the receptor to intracellular signaltransduction pathways and to adenylyl cyclase.

It is thought that the C-terminal region of CGRP initially binds to thelarge N-terminal extracellular domain (ECD) of the receptor, likelymaking interactions with both CLR and RAMP1. This initial binding eventgreatly increases the local concentration of the N-terminal region ofCGRP in the vicinity of the juxtamembrane portion of CLR, allowing theirrelatively weak interaction to occur and resulting in receptoractivation. Since mutagenesis experiments indicated that most smallmolecule antagonists interacted with the ECD of CLR/RAMP1, it washypothesized that they bind to this region of the receptor and preventthe initial binding of CGRP to the receptor. A notable exception to thismodel of peptide binding and small molecule receptor antagonism is thehydroxypyridine class of antagonists, which apparently interact withtransmembrane domain 7 (TM7) in CLR and not with the extracellulardomain (Bell I M, J. Med. Chem., 2014, 57(19), 7838-58).

The first clinically tested CGRP-RA, olcegepant, was based on adipeptide backbone, had high molecular weight, and was not orallybioavailable. Nonetheless, when dosed intravenously, olcegepant provedto be an effective antimigraine agent, and this proof-of-concept studygreatly increased interest in the field. Following the success ofolcegepant, a number of orally acting CGRP-RAs were advanced to clinicaltrials. Telcagepant and compounds BI 44370, MK-3207, and BMS-927711 haveall been used for acute treatment of migraine as oral agents. Takentogether, the results from these clinical studies demonstrate thatCGRP-RAs can exhibit similar antimigraine efficacy to the gold standardtriptan drugs but with a significantly lower incidence of adverse eventsthan is typically observed with a triptan. It is worth noting that theavailable data indicate that these CGRP blockers do not causevasoconstriction and suggest that they may have a superiorcardiovascular safety profile to the triptans. One potential concernthat has been reported with some CGRP-RAs is the observation of elevatedlevels of liver transaminases in some patients, and this reportedly ledto the discontinuation of MK-3207. Although elevated liver enzymes werealso found in a small number of subjects after dosing with telcagepantfor an extended period, it is not clear if these findings are in someway mechanism-based or specific to these two compounds.

In clinical trials for acute migraine therapy, the CGRP-RAs displayedfavorable effects, but their frequent administration was associated withliver toxicity (the elevation of liver transaminases), which limitedtheir clinical use. Hence, there is a need to develop new CGRP-RAs whichdo not induce liver injury.

SUMMARY OF THE INVENTION

One possibility to address the risk of liver injury is to target anon-oral route of delivery for a small molecule which will place a lowerburden on the liver through first-pass exposure. The compounds of theinvention can be used for sub-cutaneous, intravenous and/or intranasalroutes of administration. The molecular profile for a CGRP-RA intendedfor such routes of administration differs from the profile required foran oral molecule: extremely high affinity and functional potency,coupled with extremely high solubility is required. Disclosed herein arenovel compounds, and the first medical use of said compounds as CGRPreceptor antagonists.

Compounds of the invention include compounds of formula (I)

or salts thereof, wherein R¹ is selected from

-   R² is H or forms a spirocyclic heterocyclic ring with R³;-   R³ forms a spirocyclic heterocyclic ring with R² or is a    heterocyclic ring if R² is H.

DETAILED DESCRIPTION OF THE INVENTION

The invention relates to novel compounds. The invention also relates tothe use of novel compounds as CGRP receptor antagonists. The inventionfurther relates to the use of compounds in the manufacture ofmedicaments for use as CGRP receptor antagonists. The invention furtherrelates to compounds, compositions and medicaments for the treatment ofcerebrovascular or vascular disorders such as migraine (includingsubtypes such as: migraine without aura, chronic migraine, puremenstrual migraine, menstrually-related migraine, migraine with aura,familial hemiplegic migraine, sporadic hemiplegic migraine, basilar-typemigraine, cyclical vomiting, abdominal migraine, benign paroxysmalvertigo of childhood, retinal migraine), status migrainosus, clusterheadache, dialysis headache, paroxysmal hemicrania, osteoarthritis, hotflashes associated with menopause or medically induced menopause due tosurgery or drug treatment, hemicrania continua, cyclic vomitingsyndrome, allergic rhinitis, or rosacea. The invention further relatesto compounds, compositions and medicaments for the treatment of broaderpain states and diseases involving neurogenic inflammation includingdental pain, earache, middle ear inflammation, sunburn, joint painassociated with osteoarthritis and rheumatoid arthritis, cancer pain,fibromyalgia, diabetic neuropathy, pain associated with inflammatorybowel disease—Crohn's disease, gout, complex regional pain syndrome,Behçet's disease, endometriosis pain, back pain or cough.

Compounds exemplified herein are based around the structure: formula(I):

wherein R¹ is selected from

-   R² is H or forms a spirocyclic heterocyclic ring with R³;-   R³ forms a spirocyclic heterocyclic ring with R² or is a    heterocyclic ring if R² is H.

In a more particular embodiment, the substituent for R¹ is

In a particular embodiment, the substituent for R² is H and R³ isselected from:

In a more particular embodiment, R³ is

In a particular embodiment, R² forms a spirocyclic heterocyclic ringwith R³ to form:

Further embodiments of the invention include methods of treatmentcomprising administering a compound of formulas (I) as a CGRP receptorantagonist. The treatment using a compound of formulas (I) may be in thetreatment of cerebrovascular disorders such as migraine (includingsubtypes such as: migraine without aura, chronic migraine, puremenstrual migraine, menstrually-related migraine, migraine with aura,familial hemiplegic migraine, sporadic hemiplegic migraine, basilar-typemigraine, cyclical vomiting, abdominal migraine, benign paroxysmalvertigo of childhood, retinal migraine), status migrainosus, clusterheadache, dialysis headache, paroxysmal hemicrania, osteoarthritis, hotflashes associated with menopause or medically induced menopause due tosurgery or drug treatment, hemicrania continua, cyclic vomitingsyndrome, allergic rhinitis, or rosacea. The invention further relatesto compounds, compositions and medicaments for the treatment of broaderpain states and diseases involving neurogenic inflammation includingdental pain, earache, middle ear inflammation, sunburn, joint painassociated with osteoarthritis and rheumatoid arthritis, cancer pain,fibromyalgia, diabetic neuropathy, pain associated with inflammatorybowel disease—Crohn's disease, gout, complex regional pain syndrome,Behçet's disease, endometriosis pain, back pain or cough.

Certain novel compounds of the invention show particularly highactivities as CGRP receptor antagonists.

Exemplary compounds include:

The NMR and LCMS properties as well as the biological activities ofthese compounds are set out in Tables 2 and 3.

To the extent that any of the compounds described have chiral centres,the present invention extends to all optical isomers of such compounds,whether in the form of racemates or resolved enantiomers. The inventiondescribed herein relates to all crystal forms, solvates and hydrates ofany of the disclosed compounds however so prepared. To the extent thatany of the compounds and intermediates disclosed herein have acid orbasic centres such as carboxylates or amino groups, then all salt formsof said compounds are included herein. In the case of pharmaceuticaluses, the salt should be seen as being a pharmaceutically acceptablesalt.

Pharmaceutically acceptable salts that may be mentioned include acidaddition salts and base addition salts. Such salts may be formed byconventional means, for example by reaction of a free acid or a freebase form of a compound with one or more equivalents of an appropriateacid or base, optionally in a solvent, or in a medium in which the saltis insoluble, followed by removal of said solvent, or said medium, usingstandard techniques (e.g. in vacuo, by freeze-drying or by filtration).Salts may also be prepared by exchanging a counter-ion of a compound inthe form of a salt with another counter-ion, for example using asuitable ion exchange resin.

Examples of pharmaceutically acceptable salts include acid additionsalts derived from mineral acids and organic acids, and salts derivedfrom metals such as sodium, magnesium, or preferably, potassium andcalcium.

Examples of acid addition salts include acid addition salts formed withacetic, 2,2-dichloroacetic, adipic, alginic, aryl sulfonic acids (e.g.benzenesulfonic, naphthalene-2-sulfonic, naphthalene-1,5-disulfonic andp-toluenesulfonic), ascorbic (e.g. L-ascorbic), L-aspartic, benzoic,4-acetamidobenzoic, butanoic, (+)-camphoric, camphor-sulfonic,(+)-(1S)-camphor-10-sulfonic, capric, caproic, caprylic, cinnamic,citric, cyclamic, dodecyl sulfuric, ethane-1,2-disulfonic,ethanesulfonic, 2-hydroxyethanesulfonic, formic, fumaric, galactaric,gentisic, glucoheptonic, gluconic (e.g. D-gluconic), glucuronic (e.g.D-glucuronic), glutamic (e.g. L-glutamic), α-oxoglutaric, glycolic,hippuric, hydrobromic, hydrochloric, hydriodic, isethionic, lactic (e.g.(+)-L-lactic and (±)-DL-lactic), lactobionic, maleic, malic (e.g.(−)-L-malic), malonic, (±)-DL-mandelic, metaphosphoric, methanesulfonic,1-hydroxy-2-naphthoic, nicotinic, nitric, oleic, orotic, oxalic,palmitic, pamoic, phosphoric, propionic, L-pyroglutamic, salicylic,4-amino-salicylic, sebacic, stearic, succinic, sulfuric, tannic,tartaric (e.g. (+)-L-tartaric), thiocyanic, undecylenic and valericacids.

Particular examples of salts are salts derived from mineral acids suchas hydrochloric, hydrobromic, phosphoric, metaphosphoric, nitric andsulfuric acids; from organic acids, such as tartaric, acetic, citric,malic, lactic, fumaric, benzoic, glycolic, gluconic, succinic,arylsulfonic, pamoic acids; and from metals such as sodium, magnesium,or preferably, potassium and calcium.

Also encompassed are any solvates of the compounds and their salts.Preferred solvates are solvates formed by the incorporation into thesolid state structure (e.g. crystal structure) of the compounds of theinvention of molecules of a non-toxic pharmaceutically acceptablesolvent (referred to below as the solvating solvent). Examples of suchsolvents include water, alcohols (such as ethanol, isopropanol andbutanol) and dimethylsulfoxide. Solvates can be prepared byrecrystallising the compounds of the invention with a solvent or mixtureof solvents containing the solvating solvent. Whether or not a solvatehas been formed in any given instance can be determined by subjectingcrystals of the compound to analysis using well known and standardtechniques such as thermogravimetric analysis (TGE), differentialscanning calorimetry (DSC) and X-ray crystallography.

The solvates can be stoichiometric or non-stoichiometric solvates.Particular solvates may be hydrates, and examples of hydrates includehemihydrates, monohydrates and dihydrates.

For a more detailed discussion of solvates and the methods used to makeand characterise them, see Bryn et al., Solid-State Chemistry of Drugs,Second Edition, published by SSCI, Inc of West Lafayette, Ind., USA,1999, ISBN 0-967-06710-3.

“Pharmaceutically functional derivatives” of compounds as defined hereinincludes ester derivatives and/or derivatives that have, or provide for,the same biological function and/or activity as any relevant compound ofthe invention. Thus, for the purposes of this invention, the term alsoincludes prodrugs of compounds as defined herein.

The term “prodrug” of a relevant compound includes any compound that,following oral or parenteral administration, is metabolised in vivo toform that compound in an experimentally-detectable amount, and within apredetermined time (e.g. within a dosing interval of between 6 and 24hours (i.e. once to four times daily)).

Prodrugs of compounds may be prepared by modifying functional groupspresent on the compound in such a way that the modifications arecleaved, in vivo when such prodrug is administered to a mammaliansubject. The modifications typically are achieved by synthesizing theparent compound with a prodrug substituent. Prodrugs include compoundswherein a hydroxyl, amino, sulfhydryl, carboxyl or carbonyl group in acompound is bonded to any group that may be cleaved in vivo toregenerate the free hydroxyl, amino, sulfhydryl, carboxyl or carbonylgroup, respectively.

Examples of prodrugs include, but are not limited to, esters andcarbamates of hydroxyl functional groups, ester groups of carboxylfunctional groups, N-acyl derivatives and N-Mannich bases. Generalinformation on prodrugs may be found e.g. in Bundegaard, H. “Design ofProdrugs” p. 1-92, Elsevier, New York-Oxford (1985).

Definitions Heterocyclic

Heterocyclic means a cyclic group which may be aromatic in which atleast one ring member is other than carbon. For example, at least onering member (for example one, two or three ring members) may be selectedfrom nitrogen, oxygen and sulphur. The point of attachment of heteroarylgroups may be via any atom of the ring system. Exemplary heteroarylgroups include pyridyl, indazolyl,1,4-dihydro-2H-pyrido[2,3-d][1,3]oxazin-2-one,1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one,3,4-dihydroquinazolin-2(1H)-one, quinolin-2(1H)-one, piperidinyl,pyrrolidinyl, 2,8-diazaspiro[4.5]decane and the like.

The term “pharmaceutical composition” in the context of this inventionmeans a composition comprising an active agent and comprisingadditionally one or more pharmaceutically acceptable carriers. Thecomposition may further contain ingredients selected from, for example,diluents, adjuvants, excipients, vehicles, preserving agents, fillers,disintegrating agents, wetting agents, emulsifying agents, suspendingagents, sweetening agents, flavouring agents, perfuming agents,antibacterial agents, antifungal agents, lubricating agents anddispersing agents, depending on the nature of the mode of administrationand dosage forms. The compositions may take the form, for example, oftablets, dragees, powders, elixirs, syrups, liquid preparationsincluding suspensions, sprays, inhalants, tablets, lozenges, emulsions,solutions, cachets, granules, capsules and suppositories, as well asliquid preparations for injections, including liposome preparations.

The dosages may be varied depending upon the requirements of thepatient, the severity of the condition being treated, and the compoundbeing employed. Determination of the proper dosage for a particularsituation is within the skill of the art. Generally, treatment isinitiated with the smaller dosages which are less than the optimum doseof the compound. Thereafter the dosage is increased by small incrementsuntil the optimum effect under the circumstances is reached. Forconvenience, the total daily dosage may be divided and administered inportions during the day if desired.

The magnitude of an effective dose of a compound will, of course, varywith the nature of the severity of the condition to be treated and withthe particular compound and its route of administration. The selectionof appropriate dosages is within the ability of one of ordinary skill inthis art, without undue burden. In general, the daily dose range may befrom about 10 μg to about 30 mg per kg body weight of a human andnon-human animal, preferably from about 50 μg to about 30 mg per kg ofbody weight of a human and non-human animal, for example from about 50μg to about 10 mg per kg of body weight of a human and non-human animal,for example from about 100 μg to about 30 mg per kg of body weight of ahuman and non-human animal, for example from about 100 μg to about 10 mgper kg of body weight of a human and non-human animal and mostpreferably from about 100 μg to about 1 mg per kg of body weight of ahuman and non-human animal.

Preparation of the Compounds of the Invention

Compounds of the invention may be prepared, for example, by routesincluding those depicted in Scheme 1. Details of many of the standardtransformations such as those in the routes below and others which couldbe used to perform the same transformations can be found in standardreference textbooks such as “Organic Synthesis”, M. B. Smith,McGraw-Hill (1994) or “Advanced Organic Chemistry”, 4^(th) edition, J.March, John Wiley & Sons (1992).

Urea formations between amino acid intermediates, for example methylesters of amino acids, and amine intermediates can be formed underconditions using a coupling agent such as DSC in the presence of a basesuch as triethylamine or DIPEA in solvents such as DMF. The methyl esterportion of the subsequently formed urea derivatives can be saponifiedusing aqueous bases such as lithium hydroxide in a suitable solvent suchas THF, MeOH, 1,4-dioxane, EtOAc or a mixture thereof. The acidintermediates thus formed can be converted into amide examples understandard conditions, for example using a coupling agent such as HATU, inthe presence of a base such as DIPEA in a suitable solvent such as DMFor DCM. The amine partners for such amide couplings can be preparedusing an appropriate combination of standard transformations (forexample reductive aminations using an amine, an aldehyde or ketone, anda reducing agent such as sodium triacetoxyborohydride in a solvent suchas DCM in the presence of acetic acid; or amide formation underconditions such as those detailed above; or nucleophilic aromaticsubstitution (S_(N)Ar) reactions). In the synthesis of compounds of theinvention S_(N)Ar reactions between an amine and a halogenatedheterocycle are typically conducted at 80° C., in a suitable solventsuch as MeCN and in the presence of a base such as K₂CO₃. Followingstandard transformations such as the above, or during such a sequence ofsuch transformations, removal of standard protecting groups may benecessary and can be undertaken using conditions which can be found inreference textbooks, for example “Protecting Groups”, 3^(rd) edition, P.J. Kocieński, Georg Thieme Verlag (2005). One such transformation is theremoval of a tert-butoxycarbonyl group (commonly known as a Boc group)from an amine under acidic conditions such as HCl in a solvent such as1,4-dioxane, MeOH, EtOH, DCM or combinations thereof. It can beappreciated that Boc deprotection of amine intermediates of theinvention which possess additional basic centres may result inhydrochloride salts of different stoichiometries. For example the Bocdeprotection of an intermediate with one additional basic centre willresult in the formation of a new amine intermediate which is for examplethe mono-hydrochloride or di-hydrochloride salt, which will often beused without neutralisation of the hydrochloride salt to produce thefree base of the intermediate, as it can be appreciated that in thesubsequent amide formation an excess of a base such as DIPEA ortriethylamine is typically used to neutralise the hydrochloride salt.Amine intermediates of the invention formed by Boc-deprotection whichare used without neutralisation to the free base are named herein as thehydrochloride (×HCl), and the present invention extends to all saltforms of the said intermediates. Another such protecting group removalis the deprotection of a carbobenzyloxy-protected amine (commonly knownas a CBZ or Z group) using reductive conditions such as catalysis bypalladium on carbon in a solvent such as EtOH or aqueous EtOH in thepresence of gaseous H₂. Alternative conditions for the removal of aCBZ-protecing group include transfer hydrogenation, for example using apalladium on carbon catalyst in the presence of or ammonium formate in asolvent such as EtOH or aqueous EtOH at an elevated temperature such as70° C.

General Procedures

Where no preparative routes are included, the relevant intermediate iscommercially available. Commercial reagents were utilized withoutfurther purification. Room temperature (rt) refers to approximately20-27° C. ¹H NMR spectra were recorded at 400 MHz or 600 MHz on Bruker,Varian or JEOL instruments at ambient temperature unless otherwisespecified. Chemical shift values are expressed in parts per million(ppm), i.e. (δ)-values. The following abbreviations are used for themultiplicity of the NMR signals: s=singlet, br=broad, d=doublet,t=triplet, q=quartet, quin=quintet, h=heptet, dd=doublet of doublets,dt=double of triplets, m=multiplet. Coupling constants are listed as Jvalues, measured in Hz. NMR and mass spectroscopy results were correctedto account for background peaks. Chromatography refers to columnchromatography performed using silica and executed under positivepressure (flash chromatography) conditions. LCMS experiments werecarried out using electrospray conditions under the conditions below.LCMS data are given in the format: Mass ion, electrospray mode (positiveor negative), retention time (experimental text and Table 1); Mass ion,electrospray mode (positive or negative), retention time, approximatepurity (Table 2).

Method A. Instruments: Hewlett Packard 1100 with G1315A DAD, MicromassZQ; Column: Waters X-Bridge C-18, 2.5 micron, 2.1×20 mm or PhenomenexGemini-NX C-18, 3 micron, 2.0×30 mm; Gradient [time (min)/solvent D in C(%)]: 0.00/2, 0.10/2, 8.40/95, 10.00/95; Solvents: solvent C=2.5 LH₂O+2.5 mL 28% ammonia in water solution; solvent D=2.5 L MeCN+135 mLH₂O+2.5 mL 28% ammonia in water solution; Injection volume 1 μL; UVdetection 230 to 400 nM; column temperature 45° C.; Flow rate 1.5mL/min.

Method B. Instruments: Agilent Technologies 1260 Infinity LC withChemstation software, Diode Array Detector, Agilent 6120B SingleQuadrupole MS with API-ES Source; Column: Phenomenex Gemini-NX C-18, 3micron, 2.0×30 mm; Gradient [time (min)/solvent D in C (%)]:0.00/5,2.00/95, 2.50/95, 2.60/5, 3.00/5; Solvents C and D are as describedabove in Method A; Injection volume 0.5 μL; UV detection 190 to 400 nM;column temperature 40° C.; Flow rate 1.5 mL/min.

Abbreviations

-   DCM=dichloromethane-   DIPEA=N,N-diisopropylethylamine-   DMAC=N,N-dimethylacetamide-   DMF=dimethylformamide-   DMSO=dimethylsulfoxide-   ES=electrospray-   EtOAc=ethyl acetate-   h=hour(s)-   HATU=1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium    3-oxid hexafluorophosphate-   L=litre-   LC=liquid chromatography-   LCMS=liquid chromatography mass spectrometry-   MeCN=acetonitrile-   min=minute(s)-   MS=mass spectrometry-   NMR=nuclear magnetic resonance-   rcf=relative centrifugal force-   rpm=revolutions per minute-   rt=room temperature-   s=second(s)-   THF=tetrahydrofuran-   Prefixes n-, s-, t- and tert- have their usual meanings: normal,    secondary, iso, and tertiary.

Synthesis of Intermediates Preparation of Carboxylic Acid IntermediatesTypical Procedure for the Preparation of Carboxylic Acid Intermediatesvia Urea Formation and Subsequent Saponification, as Exemplified by thePreparation of Intermediate 6,(2R)-3-(7-methyl-1H-indazol-5-yl)-2-{[(2′-oxo-1′,2′-dihydro-1H-spiro[piperidine-4,4′-pyrido[2,3-d][1,3]oxazin]-1-yl)carbonyl]amino}propanoicacid

Step 1) Et₃N (2.26 mL, 16.3 mmol) was added to a solution of (R)-methyl2-amino-3-(7-methyl-1H-indazol-5-yl)propanoate dihydrochloride(Intermediate 5, 995 mg, 3.3 mmol) and DSC (917 mg, 3.6 mmol) in DMF (20mL) and the mixture stirred at rt for 30 min.Spiro[piperidine-4,4′-[4H]pyrido[2,3-d][1,3]oxazin]-2′(1′H)-one(Intermediate 4, 785 mg, 3.6 mmol) was then added portionwise and thereaction mixture stirred at rt for 18 h before concentration in vacuo.The residue was partitioned between H₂O and MeOH/DCM (1:9), the phaseswere separated and the aqueous layer was washed with H₂O. Residual solidfrom the separation step was dissolved in MeOH and the combined organiclayers were concentrated in vacuo and purified by flash chromatography,eluting with EtOAc in MeOH (20:1), to yield methyl(2R)-3-(7-methyl-1H-indazol-5-yl)-2-{[(2′-oxo-1′,2′-dihydro-1H-spiro[piperidine-4,4′-pyrido[2,3-d][1,3]oxazin]-1-yl)carbonyl]amino}propanoate(1.06 g, 2.22 mmol) as a white solid.

LCMS (Method A): m/z 479.3 (ES+), at 2.61 min, 100%.

¹H NMR: (400 MHz, DMSO-d₆) δ: 1.59-1.75 (m, 2H), 1.78-1.90 (m, 2H), 2.45(s, 3H), 2.90-3.08 (m, 4H), 3.59 (s, 3H), 3.86-3.96 (m, 2H), 4.28-4.38(m, 1H), 6.94-7.06 (m, 3H), 7.32 (dd, J=7.4, 1.2, 1H), 7.39 (s, 1H),7.95 (s, 1H), 8.18 (dd, J=5.1, 1.6, 1H), 10.79 (s, 1H), 13.04 (s, 1H).

Step 2) Methyl(2R)-3-(7-methyl-1H-indazol-5-yl)-2-{[(2′-oxo-1′,2′-dihydro-1H-spiro[piperidine-4,4′-pyrido[2,3-d][1,3]oxazin]-1-yl)carbonyl]amino}propanoate(1.06 g, 2.22 mmol) was dissolved in THF (15 mL) and MeOH (3 mL) and anaqueous solution of LiOH (1M, 4.4 mL, 4.4 mmol) was added dropwise.After stirring at rt for 3.5 h further aqueous LiOH (1M, 2.2 mL, 2.2mmol) was added dropwise and the mixture stirred for 1 h at rt beforeconcentration under a stream of nitrogen. The residue was dissolved in aminimum volume of H₂O and cooled to 0° C. Aqueous 1M HCl was addeddropwise to adjust the pH to ≦3 and the resulting precipitate wasisolated by filtration, washed with cold H₂O and Et₂O to yield the titlecompound (877 mg, 1.89 mmol) as a pale yellow solid.

Data in Table 1.

Intermediate 7,(2R)-3-(7-methyl-1H-indazol-5-yl)-2-({[4-(2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridin-1-yl)piperidin-1-yl]carbonyl}amino)propanoicacid

The title compound (1.50 g, 3.2 mmol) was prepared over two steps from(R)-methyl 2-amino-3-(7-methyl-1H-indazol-5-yl)propanoate (Intermediate5, 1.00 g, 4.3 mmol) and1-(piperidin-4-yl)-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one(Intermediate 1, 1.02 g, 4.7 mmol) using the methods of Intermediate 6.

Data in Table 1.

Intermediate 9,(2R)-3-(7-methyl-1H-indazol-5-yl)-2-({[4-(2-oxo-1,4-dihydroquinazolin-3(2H)-yl)piperidin-1-yl]carbonyl}amino)propanoicacid

The title compound (561 mg, 1.18 mmol) was prepared over two steps from(R)-methyl 2-amino-3-(7-methyl-1H-indazol-5-yl)propanoate (Intermediate5, 917 mg, 3.93 mmol) and3-(piperidin-4-yl)-3,4-dihydroquinazolin-2(1H)-one (Intermediate 3, 1.00g, 4.32 mmol) using the methods of Intermediate 6.

Data in Table 1.

Intermediate 8,(2R)-3-(7-methyl-1H-indazol-5-yl)-2-({[4-(2-oxo-1,2-dihydroquinolin-3-yl)piperidin-1-yl]carbonyl}amino)propanoicacid

Step 1) To a solution of (R)-methyl 2-amino-3-(7-methyl-1H-indazol-5-yl)propanoate (Intermediate 5, 6.05 g, 25.9 mmol) in DMF (60 mL) under Naat approximately −20° C. was added CDI (8.40 g, 51.8 mmol) and themixture was stirred for 15 min while keeping the temperature below −10°C. A solution of H₂O (2.34 mL) in a few mL of DMF was added and stirringcontinued for 15 min while keeping the temperature below −10° C.3-(Piperidin-4-yl) quinolin-2(1H)-one (Intermediate 2, 6.99 g, 30.6mmol), DIPEA (4.93 mL, 28.2 mmol) and DCM (20 mL) were then added inthat order and the mixture was heated to 40° C. under Na for 12 hrs.After cooling to rt, 2M HCl (aq) (38.7 mL) was added and the mixture wasextracted twice with DCM. The combined organic extracts were washedthree times with H₂O, dried (Na₂SO₄) and concentrated in vacuo.Purification by flash chromatography, eluting with MeOH/DCM (5:95),yielded methyl(2R)-3-(7-methyl-1H-indazol-5-yl)-2-({[4-(2-oxo-1,2-dihydroquinolin-3-yl)piperidin-1-yl]carbonyl}amino)propanoate(10.4 g, 21.3 mmol) as a light tan solid.

¹H NMR: (400 MHz, CDCl₃) δ: 1.40-1.60 (m, 2H), 1.95-1.97 (m, 2H), 2.46(s, 3H), 2.90-3.00 (m, 2H), 3.11-3.26 (m, 3H), 3.76 (s, 3H), 4.07-4.12(m, 2H), 4.86-4.91 (m, 1H), 5.18 (d, J=7.6, 1H), 6.93 (s, 1H), 7.17-7.21(m, 1H), 7.24 (s, 1H), 7.32 (s, 1H), 7.43-7.54 (m, 3H), 7.95 (s, 1H),10.70 (s, 2H).

Step 2) To a solution of methyl(2R)-3-(7-methyl-1H-indazol-5-yl)-2-({[4-(2-oxo-1,2-dihydroquinolin-3-yl)piperidin-1-yl]carbonyl}amino)propanoate(9.79 g, 20.1 mmol) in 1,4-dioxane (150 mL) was added a solution ofLiOH.H₂O (1.26 g, 30.0 mmol) in H₂O (150 mL) and the mixture was stirredat rt for 2 h. The reaction mixture was concentrated in vacuo tonear-dryness and re-dissolved in H₂O before being acidified with aqueous2M HCl (approximately 15 mL) whilst being rapidly stirred. The resultingthick white precipitate was isolated by filtration and washed with H₂Ountil the washings were near neutral pH. Drying in vacuo yielded thetitle compound (8.11 g, 17.1 mmol) as an off-white solid.

Data in Table 1.

Preparation of Amine Intermediates Intermediate 12, benzyl4-(2,8-diazaspiro[4.5]dec-8-yl)piperidine-1-carboxylate hydrochloride

Step 1) A mixture of tert-butyl 2,8-diazaspiro[4.5]decane-2-carboxylate(Intermediate 10, 0.50 g, 2.08 mmol), benzyl4-oxopiperidine-1-carboxylate (Intermediate 11, 583 mg, 2.50 mmol),acetic acid (143 μL, 2.50 mmol) and sodium triacetoxyborohydride (530mg, 2.50 mmol) in DCM (10 mL) was stirred at rt overnight. Furtherbenzyl 4-oxopiperidine-1-carboxylate (Intermediate 11, 600 mg, 2.57mmol) and acetic acid (150 μL, 2.62 mmol) were added and the mixturestirred at rt for 1 h before addition of further sodiumtriacetoxyborohydride (550 mg, 2.59 mmol). The mixture was stirred at rtovernight before concentration in vacuo and purification by gradientflash chromatography, eluting with 0-10% MeOH in DCM, yielded tert-butyl8-{1-[(benzyloxy)carbonyl]piperidin-4-yl}-2,8-diazaspiro[4.5]decane-2-carboxylate(620 mg, 1.35 mmol).

LCMS (Method B): m/z 458.2 (ES+), at 1.70 min.

¹H NMR: (400 MHz, CDCl₃) δ: ppm 1.45 (s, 9H), 1.48-1.56 (m, 1H),1.64-1.74 (m, 4H), 1.87-1.96 (m, 2H), 2.51-1.85 (m, 10H), 3.30-3.43 (m,4H), 4.19-4.32 (m, 2H), 5.11 (s, 2H), 7.30-7.40 (m, 5H).

Step 2) HCl in 1,4-dioxane (4M, 5.0 mL, 20.0 mmol) was added to asolution of (tert-butyl8-{1-[(benzyloxy)carbonyl]piperidin-4-yl}-2,8-diazaspiro[4.5]decane-2-carboxylate(310 mg, 0.68 mmol) in MeOH (5 mL). The mixture was stirred at rt for 3d before concentration in vacuo yielded the title compound (colourlesssolid, 290 mg).

Data in Table 1.

Intermediate 14, benzyl[(2R)-1-(2,8-diazaspiro[4.5]dec-8-yl)-1-oxopropan-2-yl]methylcarbamatehydrochloride

Step 1) A mixture of tert-butyl 2,8-diazaspiro[4.5]decane-2-carboxylate(Intermediate 10, 865 mg, 3.60 mmol),N-[(benzyloxy)carbonyl]-N-methyl-D-alanine (Intermediate 13, 712 mg,3.00 mmol), HATU (1.37 g, 3.60 mmol) and DIPEA (2.68 mL, 15.0 mmol) inDCM (25 mL) was stirred at rt overnight. Saturated aqueous NaHCO₃solution was added, the phases were separated and the organic phases wasconcentrated in vacuo. Purification by gradient flash chromatography,eluting with 2-10% MeOH in DCM, followed by preparative HPLC (PhenomenexGemini-NX 5 μm C18 column, 100×30 mm, eluting with 50 to 80%MeCN/Solvent B over 12.5 min at 30 mL/min [where solvent B is 0.2% of(28% NH₃/H₂O) in H₂O], collecting fractions by monitoring at 205 nm),yielded tert-butyl8-{N-[(benzyloxy)carbonyl]-N-methyl-D-alanyl}-2,8-diazaspiro[4.5]decane-2-carboxylateas a colourless foam (1.08 g, 2.19 mmol).

LCMS (Method A): m/z 460.5 (ES+), at 4.68 min.

¹H NMR: (400 MHz, DMSO-d₆) δ: 1.10-1.29 (m, 5H), 1.30-1.47 (m, 1H), 1.39(s, 9H), 1.52-1.77 (m, 2H), 2.67-2.77 (m, 3H), 2.87-3.12 (m, 3H),3.12-3.35 (m, 5H), 3.46-3.76 (m, 1H), 4.88-5.09 (m, 2H), 5.12-5.22 (m,1H), 7.25-7.42 (m, 5H).

Step 2) The title compound (white foam, 1.08 g) was prepared from Step 1material (1.08 g, 2.19 mmol) and 4M HCl in 1,4-dioxane (15 mL, 60.0mmol) in MeOH (15 mL) using the methods of Intermediate 12.

Data in Table 1.

Intermediate 16, 8-(pyridin-4-yl)-2,8-diazaspiro[4.5]decanehydrochloride

Step 1) A mixture of tert-butyl 2,8-diazaspiro[4.5]decane-2-carboxylate(Intermediate 10, 1.00 g, 4.16 mmol), 4-fluoropyridine hydrochloride(Intermediate 15, 614 mg, 4.60 mmol) and K₂CO₃ (1.74 g, 12.6 mmol) inMeCN (80 mL) was heated at 80° C. overnight before cooling to rt andconcentration in vacuo. The residue was partitioned between EtOAc andH₂O, the organic phase was washed with brine, dried (MgSO₄), andconcentrated in vacuo. Purification by gradient flash chromatography,eluting with 0-100% solvent B in DCM (where solvent B is 7N NH₃ inMeOH/DCM, 1:9) yielded tert-butyl8-(pyridin-4-yl)-2,8-diazaspiro[4.5]decane-2-carboxylate (610 mg, 1.92mmol) as a brown, viscous oil.

LCMS (Method B): m/z 318.2 (ES+), at 1.36 min.

¹H NMR: (400 MHz, CD₃OD) δ: 1.46 (s, 9H), 1.63-1.68 (m, 4H), 1.81-1.85(m, 2H), 3.23 (s 2H), 3.36-3.54 (m, 6H), 6.82-6.83 (m, 2H), 8.07-8.09(m, 2H).

Step 2) The title compound (brown oil, 550 mg) was prepared from step 1)material (610 mg, 1.92 mmol) and 4M HCl in 1,4-dioxane (10 mL) using themethods of Intermediate 12, and used without purification in thepreparation of Example 7.

Data in Table 1.

TABLE 1 Intermediate Name Data 1 1-(piperidin-4-yl)-1,3-dihydro-2H-Commercially available, CAS No. 185961-99-3 imidazo[4,5-b]pyridin-2-one2 3-(piperidin-4-yl)quinolin-2(1H)- Commercially available, CAS No.205058-78-2 one 3 3-(piperidin-4-yl)-3,4- Commercially available, CASNo. 79098-75-2 dihydroquinazolin-2(1H)-one 4spiro[piperidine-4,4′-[4H]pyrido[2, Commercially available, CAS No.753440-87-8 3-d][1,3]oxazin]-2′(1′H)-one 5 (R)-methyl2-amino-3-(7-methyl- Commercially available, CAS No. No. 890044-1H-indazol-5-yl)propanoate 58-3 (free base), CAS No. No. 1414976-14-9(dihydrochloride salt) 6 (2R)-3-(7-methyl-1H-indazol-5- LCMS (Method A):m/z 463.5 (ES−), yl)-2-{[(2′-oxo-1′,2′-dihydro-1H- 465.3 (ES+), at 0.10min. ¹H NMR (400 MHz, DMSO- spiro[piperidine-4,4′-pyrido[2,3- d₆) δ:1.53-1.91 (m, 4H), 2.44 (s, 3H), d][1,3]oxazin]-1- 2.89-3.14 (m, 5H),3.89 (t, J = 11.5, 2H), 4.23 (br s, 1H), yl)carbonyl]amino}propanoicacid 6.73 (d, J = 7.8, 1H), 6.93-7.06 (m, 2H), 7.31 (d, J = 7.4, 1H),7.38 (s, 1H), 7.93 (s, 1H), 8.17 (dd, J = 5.1, 1.2, 1H), 10.78 (s, 1H),13.00 (br s, 1H) 7 (2R)-3-(7-methyl-1H-indazol-5- LCMS (Method A): m/z464.1 (ES+), at 1.14 min. yl)-2-({[4-(2-oxo-2,3-dihydro-1H- ¹H NMR (400MHz, DMSO-d₆) δ: imidazo[4,5-b]pyridin-1- 1.62-1.67 (m, 2H), 1.87-2.12(m, 2H), 2.38-2.52 (m, yl)piperidin-1- 1H), 2.46 (s, 3H), 2.70-2.80 (m,2H), 2.98 (dd, yl]carbonyl}amino)propanoic acid J = 13.7, 9.8, 1H), 3.09(dd, J = 13.7, 4.3, 1H), 4.08 (br d, J = 12.9, 2H), 4.20-4.27 (m, 1H),4.28-4.38 (m, 1H), 6.75 (d, J = 8.2, 1H), 6.88 (dd, J = 7.8, 5.5, 1H),7.42 (s, 1H), 7.27 (d, J = 7.8, 1H), 7.42 (s, 1H), 7.88 (dd, J = 5.1,1.2, 1H), 7.96 (s, 1H), 11.54 (br s, 1H), 12.99 (br s, 1H) 8(2R)-3-(7-methyl-1H-indazol-5- LCMS (Method A): m/z 474.3 (ES+), at 1.82min. yl)-2-({[4-(2-oxo-1,2- ¹H NMR (400 MHz, DMSO-d₆) δ:dihydroquinolin-3-yl)piperidin-1- 1.25-1.36 (m, 2H), 1.72-1.78 (m, 2H),2.48 (s, 3H), yl]carbonyl}amino)propanoic acid 2.66-2.78 (m, 2H),2.88-2.94 (m, 1H), 2.97-3.03 (m, 1H), 3.10 (dd, J = 8.4, 3.4, 1H), 4.08(d, J = 12.0, 2H), 4.24-4.30 (m, 1H), 6.57 (d, J = 8.0, 1H), 7.04 (s,1H), 7.15 (dd, J = 12.4, 1.2, 1H), 7.27 (d, J = 8.4, 1H), 7.41-7.45 (m,2H), 7.54 (s, 1H), 7.62 (dd, J = 6.8, 1.2, 1H), 7.97 (s, 1H), 11.69 (s,1H), 12.1-13.1 (br s, 2H) 9 (2R)-3-(7-methyl-1H-indazol-5- LCMS (MethodA): m/z 475.4 (ES−), yl)-2-({[4-(2-oxo-1,4- 477.3 (ES+), at 0.66 min. ¹HNMR (400 MHz, DMSO- dihydroquinazolin-3(2H)- d₆) δ: 1.36-1.66 (m, 4H),2.47 (s, 3H), yl)piperidin-1- 2.59-2.78 (m, 2H), 2.92-3.14 (m, 3H), 4.00(t, J = 16.0, 2H), yl]carbonyl}amino)propanoic acid 4.06-4.20 (m, 2H),4.20-4.33 (m, 1H), 6.47 (br s, 1H), 6.75 (d, J = 7.8, 1H), 6.86 (t, J =7.4, 1H), 7.01 (s, 1H), 7.06-7.17 (m, 2H), 7.36 (s, 1H), 7.96 (s, 1H),9.21 (s, 1H), 12.99 (s, 1H) 10 tert-butyl 2,8- Commercially available,CAS No. 336191-17-4 diazaspiro[4.5]decane-2- carboxylate 11 benzyl4-oxopiperidine-1- Commercially available, CAS No. 19099-93-5carboxylate 12 benzyl 4-(2,8-diazaspiro[4.5]dec-8- LCMS (Method B): m/z358.2 (ES+), at 1.51 min. yl)piperidine-1-carboxylate ¹H NMR (400 MHz,DMSO-d₆) δ: ppm 1.49-1.59 (m, 2H), 1.74-1.80 (m, 2H), 1.85-1.96 (m, 4H),2.07-2.10 (m, 2H), 2.88-2.96 (m, 4H), 3.11-3.13 (m 1H), 3.18-3.26 (m,2H), 3.28-3.34 (m, 4H), 4.09-4.13 (m, 2H), 5.06 (s, 2H), 7.30-7.38 (m,5H), 9.22-9.33 (m, 2H), 10.38-10.95 (m, 1H) 13N-[(benzyloxy)carbonyl]-N-methyl- Commercially available, CAS No.68223-03-0 D-alanine 14 benzyl [(2R)-1-(2,8- LCMS (Method A): m/z 360.4(ES+), at 5.21 min. diazaspiro[4.5]dec-8-yl)-1- ¹H NMR (400 MHz,DMSO-d₆) δ: oxopropan-2-yl]methylcarbamate 1.09-1.22 (m, 3H), 1.22-1.57(m, 4H), 1.59-1.87 (m, 2H), 2.68-2.80 (m, 3H), 2.82-3.08 (m, 2H),3.11-3.33 (m, 4H), 3.56 (s, 3H), 4.86-5.22 (m, 3H), 7.10-7.57 (m, 5H),9.20 (br s, 2H) 15 4-fluoropyridine hydrochloride Commerciallyavailable, CAS No. 39160-31-1 16 8-(pyridin-4-yl)-2,8- LCMS (Method B):m/z 218.2 (ES+), at 0.91 min. diazaspiro[4.5]decane ¹H NMR: (400 MHz,CD₃OD) δ: 1.81-1.85 (m, hydrochloride 4H), 2.05-2.09 (m, 2H), 3.23 (s,2H), 3.43-3.47 (m, 2H), 3.70-3.84 (m, 4H), 7.19-7.21 (m, 2H), 8.11-8.13(m, 2H) (exchangeable protons not observed)

SYNTHESIS OF EXAMPLES

Typical procedures for the preparation of examples via amide coupling,and where appropriate, deprotection, as exemplified by the preparationof the below examples.

Procedure 1: Example 2N-[(2R)-1-[8-(N-methyl-D-alanyl)-2,8-diazaspiro[4.5]dec-2-yl]-3-(7-methyl-1H-indazol-5-yl)-1-oxopropan-2-yl]-4-(2-oxo-1,2-dihydroquinolin-3-yl)piperidine-1-carboxamide

Step 1) A mixture of(2R)-3-(7-methyl-1H-indazol-5-yl)-2-({[4-(2-oxo-1,2-dihydroquinolin-3-yl)piperidin-1-yl]carbonyl}amino)propanoicacid (Intermediate 8, 100 mg, 0.21 mmol), benzyl[(2R)-1-(2,8-diazaspiro[4.5]dec-8-yl)-1-oxopropan-2-yl]methylcarbamatehydrochloride (Intermediate 14, 99 mg, 0.25 mmol), HATU (96 mg, 0.25 mL)and DIPEA (146 μL, 0.84 mmol) in DMF (5 mL) was stirred at rt overnightbefore concentration in vacuo. Purification by gradient flashchromatography, eluting with 0-10% MeOH in DCM yielded benzylmethyl[(2R)-1-{2-[(2R)-3-(7-methyl-1H-indazol-5-yl)-2-({[4-(2-oxo-1,2-dihydroquinolin-3-yl)piperidin-1-yl]carbonyl}amino)propanoyl]-2,8-diazaspiro[4.5]dec-8-yl}-1-oxopropan-2-yl]carbamate(160 mg, 0.20 mmol) as a pale yellow solid.

LCMS (Method B): m/z 815.2 (ES+), at 1.41 min, 95%.

Step 2) Ammonium formate (126 mg, 2.0 mmol) was added to a mixture ofbenzylmethyl[(2R)-1-{2-[(2R)-3-(7-methyl-1H-indazol-5-yl)-2-({[4-(2-oxo-1,2-dihydroquinolin-3-yl)piperidin-1-yl]carbonyl}amino)propanoyl]-2,8-diazaspiro[4.5]dec-8-yl}-1-oxopropan-2-yl]carbamate(160 mg, 0.20 mmol) in EtOH (10 mL) and H20 (2 mL). Palladium on carbon(10%, 10 mg) was added and the reaction mixture was heated at 70° C.overnight. After cooling to rt further ammonium formate (126 mg, 2.0mmol) and palladium on carbon (10%, 10 mg) were added and the mixtureheated at 70° C. for 1 h before cooling to rt, filtration throughcelite, and concentration of the filtrate in vacuo. Purification bygradient flash chromatography eluting with 0-10% MeOH in DCM, followedby preparative HPLC (Phenomenex Gemini-NX 5 μm C18 column, 100×30 mm,eluting with 20 to 40% MeCN/Solvent B over 12.5 min at 30 mL/min [wheresolvent B is 0.2% of (28% NH₃/H₂O) in H₂O], collecting fractions bymonitoring at 205 nm), yielded the title compound (20 mg, 0.03 mmol) asa colourless solid.

Data in Table 2.

Procedure 2:

Example 5N-[(2R)-1-[8-(N-methyl-D-alanyl)-2,8-diazaspiro[4.5]dec-2-yl]-3-(7-methyl-1H-indazol-5-yl)-1-oxopropan-2-yl]-2′-oxo-1′,2′-dihydro-1H-spiro[piperidine-4,4′-pyrido[2,3-d][1,3]oxazine]-1-carboxamide

Step 1) Benzylmethyl[(2R)-1-{2-[(2R)-3-(7-methyl-1H-indazol-5-yl)-2-{[(2′-oxo-1′,2′-dihydro-1H-spiro[piperidine-4,4′-pyrido[2,3-d][1,3]oxazin]-1-yl)carbonyl]amino}propanoyl]-2,8-diazaspiro[4.5]dec-8-yl}-1-oxopropan-2-yl]carbamate(26 mg, 0.03 mg) was prepared from(2R)-3-(7-methyl-1H-indazol-5-yl)-2-{[(2′-oxo-1′,2′-dihydro-1H-spiro[piperidine-4,4′-pyrido[2,3-d][1,3]oxazin]-1-yl)carbonyl]amino}propanoicacid (Intermediate 6, 70 mg, 0.15 mmol), benzyl[(2R)-1-(2,8-diazaspiro[4.5]dec-8-yl)-1-oxopropan-2-yl]methylcarbamatehydrochloride (Intermediate 14, 71 mg, 0.18 mmol), HATU (68 mg, 0.18mmol) and DIPEA (0.13 mL, 0.18 mmol) in DMF (2 mL) using the methods ofExample 2, Step 1.

LCMS (Method A): m/z 806.7 (ES+), at 3.64 min.

¹H NMR: (400 MHz, CD₃OD) δ: ppm 0.17-1.06 (m, 2H), 1.06-1.47 (m, 7H),1.47-1.75 (m, 1H), 1.76-1.96 (m, 1H), 2.03 (d, J=5.1, 3H), 2.19-2.43 (m,1H), 2.52 (s, 3H), 2.69-2.96 (m, 5H), 2.96-3.24 (m, 7H), 3.40-3.55 (m,1H), 3.55-3.97 (m, 1H), 4.07 (d, J=10.5, 2H), 4.52-4.74 (m, 1H),4.97-5.12 (m, 1H), 5.13-5.33 (m, 1H), 6.93-7.19 (m, 3H), 7.20-7.65 (m,9H), 7.89-8.06 (m, 1H), 8.20 (d, J=4.7, 1H).

Step 2) A mixture of benzylmethyl[(2R)-1-{2-[(2R)-3-(7-methyl-1H-indazol-5-yl)-2-{[(2′-oxo-1′,2′-dihydro-1H-spiro[piperidine-4,4′-pyrido[2,3-d][1,3]oxazin]-1-yl)carbonyl]amino}propanoyl]-2,8-diazaspiro[4.5]dec-8-yl}-1-oxopropan-2-yl]carbamate(26 mg, 0.03 mg) and palladium on carbon (10%, 10 mg) in EtOH (2.5 mL)and H₂O (0.5 mL) was stirred at rt overnight under an atmosphere of H₂.After removal of the H₂ atmosphere the mixture was filtered throughcelite and the filtrate concentrated in vacuo to yield the titlecompound (22 mg, 0.03 mmol).

Data in Table 2.

Further examples prepared by the above procedures are detailed in Table2.

TABLE 2 Ex. Intermediates/ LCMS data No. Name Procedure ¹H NMR (MethodA) 1 N-{(2R)-3-(7-methyl-1H- 7, 12 (400 MHz, CD₃OD) δ: ppm m/z 669.4indazol-5-yl)-1-oxo-1-[8- Procedure 1 0.42-0.59 (m, 2H), 0.67-0.79 (m,1H), (ES⁺), at (piperidin-4-yl)-2,8- 0.87-0.95 (m, 1H), 1.10-1.49 (m,4H), 1.86 min, diazaspiro[4.5]dec-2- 1.51-1.60 (m, 1H), 1.63-1.72 (m,1H), 95% yl]propan-2-yl}-4-(2-oxo- 1.76-1.89 (m, 3H), 1.91-2.13 (m, 2H),2,3-dihydro-1H- 2.13-2.43 (m, 4H), 2.52-2.59 (m, 5H),imidazo[4,5-b]pyridin-1- 2.76-3.00 (m, 5H), 3.04-3.16 (m, 4H),yl)piperidine-1- 3.53-3.75 (m, 1H), 4.25-4.32 (m, 2H), carboxamide4.46-4.53 (m, 1H), 4.59-4.70 (m, 1H), 7.01-7.06 (m, 1H), 7.10-7.16 (m,1H), 7.46-7.47 (m, 1H), 7.52-7.57 (m, 1H), 7.92-7.94 (m, 1H), 7.98-8.03(m, 1H) (4 exchangeable protons not observed) 2N-[(2R)-1-[8-(N-methyl-D- 8, 14 (600 MHz, DMSO-d₆, spectrum m/z 681.7alanyl)-2,8- Procedure 1 recorded at 353K): δ: ppm (ES⁺), atdiazaspiro[4.5]dec-2-yl]-3- 0.83-0.96 (m, 2H), 1.04 (br s, 2H), 1.05 (brs, 3.33 min, (7-methyl-1H-indazol-5- 1H), 1.32-1.54 (m, 5H), 1.56-1.67(m, 100% yl)-1-oxopropan-2-yl]-4- 1H), 1.75-1.84 (m, 2H), 2.16 (br s,2H), (2-oxo-1,2- 2.17 (br s, 1H), 2.49 (s, 3H), dihydroquinolin-3-2.70-2.84 (m, 3H), 2.89-2.99 (m, 4H), yl)piperidine-1- 3.06-3.15 (m,2H), 3.25-3.35 (m, 1H), carboxamide 3.36-3.52 (m, 3H), 3.65-3.77 (m,1H), 4.12 (t, J = 13.8, 2H), 4.61 (q, J = 7.8, 1H), 6.29 (br s, 1H),7.01 (s, 1H), 7.13 (ddd, J = 7.8, 7.0, 1.1, 1H), 7.29 (d, J = 8.3, 1H),7.38 (s, 1H), 7.41 (ddd, J = 8.3, 7.1, 1.5, 1H), 7.57 (s, 1H), 7.60 (dd,J = 7.8, 1.0, 1H), 7.94 (s, 1H) (3 exchangeable protons not observed) 3N-[(2R)-1-[8-(N-methyl-D- 7, 14 (400 MHz, CD₃OD) δ: ppm m/z 671.5alanyl)-2,8- Procedure 1 0.44-0.72 (m, 1H), 0.77-0.94 (m, 1H), (ES⁺), atdiazaspiro[4.5]dec-2-yl]-3- 1.07-1.20 (m, 3H), 1.34-1.54 (m, 2H), 2.57min, (7-methyl-1H-indazol-5- 1.57-1.68 (m, 1H), 1.77-1.89 (m, 2H), 2.20(s, 95%. yl)-1-oxopropan-2-yl]-4- 3H), 2.29-2.47 (m, 2H), 2.54 (s, 3H),(2-oxo-2,3-dihydro-1H- 2.73-2.82 (m, 1H), 2.90-3.02 (m, 2H),imidazo[4,5-b]pyridin-1- 3.06-3.45 (m, 7H), 3.49-3.59 (m, 3H),yl)piperidine-1- 3.63-3.81 (m, 1H), 4.25-4.28 (m, 2H), carboxamide4.43-4.55 (m, 1H), 4.60-4.71 (m, 1H), 7.00-7.05 (m, 1H), 7.10-7.16 (m,1H), 7.46-7.55 (m, 2H), 7.90-8.02 (m, 2H) (4 exchangeable protons notobserved) 4 N-{(2R)-3-(7-methyl-1H- 9, 12 (400 MHz, DMSO-d₆) δ: ppm m/z682.6 indazol-5-yl)-1-oxo-1-[8- Procedure 2 0.46-0.99 (m, 3H), 1.00-1.27(m, 2H), (ES⁺), at (piperidin-4-yl)-2,8- 1.32 (br s, 3H), 1.40-1.66 (m,7H), 3.33 min, diazaspiro[4.5]dec-2- 1.89-2.10 (m, 2H), 2.10-2.25 (m,2H), 99%. yl]propan-2-yl}-4-(2-oxo- 2.27-2.43 (m, 3H), 2.45 (d, J = 2.3,3H), 1,4-dihydroquinazolin- 2.57-2.75 (m, 3H), 2.77-3.01 (m, 5H),3(2H)-yl)piperidine-1- 3.01-3.18 (m, 2H), 3.97-4.20 (m, 4H), carboxamide4.44 (quin, J = 7.5, 1H), 6.67-6.90 (m, 3H), 6.98 (d, J = 4.7, 1H),7.03-7.22 (m, 3H), 7.36 (br s, 1H), 7.96 (s, 1H), 9.21 (s, 1H), 13.02(d, J = 9.0, 1H) 5 N-[(2R)-1-[8-(N-methyl-D- 6, 14 (400 MHz, CD₃OD) δ:ppm m/z 670.6 alanyl)-2,8- Procedure 2 0.37-0.62 (m, 1H), 0.62-1.01 (m,1H), 1.13 (t, (ES⁻), 672.6 diazaspiro[4.5]dec-2-yl]-3- J = 6.2, 3H),1.28 (s, 1H), 1.34-1.56 (m, (ES⁺), at (7-methyl-1H-indazol-5- 3H),1.56-1.77 (m, 1H), 1.81-1.99 (m, 2.60 min, yl)-1-oxopropan-2-yl]-2′-1H), 1.99-2.14 (m, 3H), 2.17-2.27 (m, 100%. oxo-1′,2′-dihydro-1H- 4H),2.43-2.53 (m, 1H), 2.54 (s, 3H), spiro[piperidine-4,4′- 2.70-2.94 (m,1H), 2.95-3.26 (m, 5H), pyrido[2,3- 3.37-3.81 (m, 4H), 4.07 (d, J =13.3, d][1,3]oxazine]-1- 2H), 4.54-4.76 (m, 1H), 6.95-7.21 (m,carboxamide 2H), 7.37-7.52 (m, 1H), 7.53-7.65 (m, 1H), 8.00 (d, J =10.2, 1H), 8.21 (d, J = 4.7, 1H) (4 exchangeable protons not observed) 6N-[(2R)-1-[8-(N-methyl-D- 9, 14 (400 MHz, DMSO-d₆) δ: ppm m/z 684.7alanyl)-2,8- Procedure 2 0.39-0.94 (m, 2H), 0.98 (br s, 3H), (ES⁺), atdiazaspiro[4.5]dec-2-yl]-3- 1.16-1.41 (m, 3H), 1.41-1.65 (m, 5H), 3.08min, (7-methyl-1H-indazol-5- 1.98-2.17 (m, 3H), 2.46 (s, 3H), 2.57-2.80(m, 100%. yl)-1-oxopropan-2-yl]-4- 3H), 2.81-3.26 (m, 8H), 3.38-3.58 (m,(2-oxo-1,4- 2H), 3.61-3.77 (m, 1H), 3.89-4.21 (m,dihydroquinazolin-3(2H)- 3H), 4.21-4.31 (m, 1H), 4.41-4.51 (m,yl)piperidine-1- 1H), 6.74 (d, J = 7.8, 1H), 6.85 (t, J = 7.4,carboxamide 2H), 6.94-7.22 (m, 4H), 7.34-7.43 (m, 1H), 7.98 (d, J = 6.6,1H), 9.23 (s, 1H), 13.07 (br s, 1H) 7 N-{(2R)-3-(7-methyl-1H- 7, 16 (400MHz, CD₃OD) δ: ppm m/z 663.6 indazol-5-yl)-1-oxo-1-[8- Procedure 1,1.48-1.56 (m, 3H), 1.61-1.68 (m, 2H), (ES⁺), at (pyridin-4-yl)-2,8- Step1 1.83-1.84 (m, 2H), 2.22-2.43 (m, 3H), 2.93 min, diazaspiro[4.5]dec-2-2.51-2.58 (m, 3H), 2.91-3.13 (m, 7H), 99%. yl]propan-2-yl}-4-(2-oxo-3.21-3.27 (m, 1H), 3.37-3.48 (m, 3H), 2,3-dihydro-1H- 3.52-3.63 (m, 1H),4.23-4.31 (m, 2H), imidazo[4,5-b]pyridin-1- 4.45-4.51 (m, 1H), 4.67-4.75(m, 1H), yl)piperidine-1- 6.66-6.76 (m, 2H), 7.02-7.08 (m, 1H),carboxamide 7.13-7.17 (m, 1H), 7.49-7.57 (m, 2H), 7.94-7.96 (m, 1H),8.03-8.10 (m, 3H) (3 exchangeable protons not observed)

Biological Methods

Cloning, Baculovirus generation, large-scale infection of Sf21 cells andmembrane preparation. Human Calcitonin Receptor Like Receptor (CRLR) andhuman RAMP1 were cloned into Invitrogen's (ThermoFisher Scientific, UK)pFastBac dual expression vector. Transposition of CRLR/RAMP1 DNA wasperformed using Invitrogen's Bac-to-Bac Baculovirus Expression Systems.P0 baculovirus was generated by transfecting SF9 cells with bacmid DNAusing Cellfectin® II transfection reagent (ThermoFisher Scientific, UK,catalog number 10362-100). Following P0 generation P1 virus was thengenerated ready for large scale infection and membrane preparation. Sf21cells were grown in expression medium ESF921 (Expression Systems, USA,catalog number 96-001-01) supplemented with 10% heat-inactivated FBS and1% Pen/Strep and were infected at a cell density of 2.5×10⁶ cells/mL andan MOI of 2. Expression was carried out over 48 h in a shaking incubatorset at 27° C. The cell culture was centrifuged at 2,500 rcf for 10 minat 4° C. The pellets were resuspended in cold PBS supplemented withRoche's Complete EDTA-free protease inhibitor cocktail tablets (RocheApplied Sciences, catalog number 05056489001), 1 mM PMSF and 1 mM EDTA.The resuspended cell paste was then centrifuged at 3,273 rcf for 12 minat 4° C. The supernatant was discarded and the pellet frozen at −80° C.The cell pellet from a 4 L culture was resuspended in buffer containing50 mM Hepes pH 7.5, 150 mM NaCl, 8 Roche EDTA-free protease inhibitorcocktail tablets and 1 mM PMSF. The suspension was left stirring at rtfor 1 h and then homogenised for 90 s at 9,500 rpm using a VDI 25 (VWR,USA) homogeniser. The cells were then lysed using a Microfluidizerprocessor M-110L Pneumatic (Microfluidics, USA). After lysis, themixture was homogenised for 90 s at 9,500 rpm and then centrifuged at335 rcf for 10 min. The supernatant was then further ultra-centrifugedat 42,000 rpm for 90 min. After ultra-centrifugation, the supernatantwas discarded and the pellet was resuspended in 50 mL (25 mL for each 2L culture) of buffer containing 50 mM Hepes pH 7.5, 150 mM NaCl, 3 RocheEDTA-free protease inhibitor cocktail tablets and 1 mM PMSF. Thesuspension was then homogenised for 90 s at 9,500 rpm. The resultingmembranes were then stored at −80° C.

Radioligand binding assay. Human CGRP receptors (consisting of CRLR andRAMP1) expressed in insect Sf21 cell membrane homogenates werere-suspended in the binding buffer (10 mM HEPES, pH 7.4, 5 mM MgCl₂,0.2% BSA) to a final assay concentration of 0.6 protein per well.Saturation isotherms were determined by the addition of variousconcentrations of ³H-telcagepant (Ho et al, The Lancet, 2008, 372, 2115)(in a total reaction volume of 250 μL) for 60 min at rt. At the end ofthe incubation, membranes were filtered onto a unifilter, a 96-wellwhite microplate with bonded GF/B filter pre-incubated with 0.5% PEI,with a Tomtec cell harvester and washed 5 times with distilled water.Non-specific binding (NSB) was measured in the presence of 10 nM MK-3207hydrochloride (CAS No. 957116-20-0). Radioactivity on the filter wascounted (1 min) on a microbeta counter after addition of 50 μL ofscintillation fluid. For inhibition experiments, membranes wereincubated with 0.5 nM ³H-telcagepant and 10 concentrations of theinhibitory compound (0.001-10 μM). IC₅₀ values were derived from theinhibition curve and the affinity constant (K_(i)) values werecalculated using the Cheng-Prussoff equation (Cheng et al, Biochem.Pharmacol. 1973, 22, 3099-3108). The pK_(i) values (where pK_(i)=−log₁₀K_(i)) of certain compounds of the invention are detailed in Table 3.

cAMP functional assay. cAMP production following receptor activation wasdetermined using the Homogeneous Time-Resolved Fluorescence (HTRF) cAMPdynamic-2 assay (Cisbio, France). The human neuroblastoma cell lineSK-N-MC endogenously expressing the human CGRP receptor was seeded at adensity of 12,500 cells/well in solid walled 96 well half area plates(Costar, Catalog Number 3688, Corning Life Sciences, Germany). After 16h incubation at 37° C. media was removed and cells were incubated at 37°C. for 30 min in serum free media containing 500 μM IBMX (Tocris,Abingdon, UK, Catalog Number 2845) and increasing concentrations of testantagonist. Following this cells were challenged with an EC₈₀concentration of human CGRP (0.3 nM) for a further 30 min at 37° C. andthen cAMP production was determined as manufacturer's instructionsbefore plates were read on a PheraStar fluorescence plate reader (BMGLabTech, Germany). IC₅₀ values were derived from the inhibition curve.The pIC₅₀ values (where pIC₅₀=−log₁₀ IC₅₀) were converted to afunctional pK_(b) value using a modified Cheng-Prussoff equation whereK_(d)=agonist EC₅₀ and L hot=agonist challenge concentration. The pK_(b)values of certain compounds of the invention are detailed in Table 3.

TABLE 3 Ex- ample pK_(i) pK_(b) No. Name Structure average average 1N-{(2R)-3-(7-methyl-1H- indazol-5-yl)-1-oxo-1-[8- (piperidin-4-yl)-2,8-diazaspiro[4.5]dec-2- yl]propan-2-yl}-4-(2-oxo- 2,3-dihydro-1H-imidazo[4,5-b]pyridin-1- yl)piperidine-1- carboxamide

9.8 9.6 2 N-[(2R)-1-[8-(N-methyl- D-alanyl)-2,8-diazaspiro[4.5]dec-2-yl]- 3-(7-methyl-1H-indazol-5-yl)-1-oxopropan-2-yl]- 4-(2-oxo-1,2- dihydroquinolin-3-yl)piperidine-1- carboxamide

9.8 8.9 3 N-[(2R)-1-[8-(N-methyl- D-alanyl)-2,8-diazaspiro[4.5]dec-2-yl]- 3-(7-methyl-1H-indazol-5-yl)-1-oxopropan-2-yl]- 4-(2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridin-1- yl)piperidine-1- carboxamide

10.1 9.2 4 N-{(2R)-3-(7-methyl-1H- indazol-5-yl)-1-oxo-1-[8-(piperidin-4-yl)-2,8- diazaspiro[4.5]dec-2- yl]propan-2-yl}-4-(2-oxo-1,4-dihydroquinazolin- 3(2H)-yl)piperidine-1- carboxamide

10.1 9.1 5 N-[(2R)-1-[8-(N-methyl- D-alanyl)-2,8-diazaspiro[4.5]dec-2-yl]- 3-(7-methyl-1H-indazol-5-yl)-1-oxopropan-2-yl]- 2′-oxo-1′,2′-dihydro-1H- spiro[piperidine-4,4′-pyrido[2,3-d][1,3] oxazine]-1-carboxamide

10.0 9.3 6 N-[(2R)-1-[8-(N-methyl- D-alanyl)-2,8-diazaspiro[4.5]dec-2-yl]- 3-(7-methyl-1H-indazol-5-yl)-1-oxopropan-2-yl]- 4-(2-oxo-1,4- dihydroquinazolin-3(2H)-yl)piperidine-1- carboxamide

9.8 9.2 7 N-{(2R)-3-(7-methyl-1H- indazol-5-yl)-1-oxo-1-[8-(pyridin-4-yl)-2,8- diazaspiro[4.5]dec-2- yl]propan-2-yl}-4-(2-oxo-2,3-dihydro-1H- imidazo[4,5-b]pyridin-1- yl)piperidine-1- carboxamide

10.3 9.4

Pharmacokinetic profiling. The pharmacokinetic profiles of Examples andreference compounds have been assessed in male Sprague Dawley® rats viaintravenous (iv), sub-cutaneous (sc) and intranasal (IN) routes ofdelivery, and in male Cynomolgus Monkeys via iv and sc routes ofdelivery. Pharmacokinetic data for Examples of the invention and areference compound, olcegepant, are detailed in Tables 4 and 5.

-   Methods: For rat studies, groups of three male Sprague Dawley® rats,    typically ranging in weight between 180 and 300 g, were given a    single dose of Example or reference compound via one of the    following routes: iv, sc or IN, using doses, dose volumes and    vehicles specified in Table 4. Prior to IN dosing rats were    anaesthetised with an intramuscular dose of 25-30 mg/kg ketamine    cocktail (ketamine, xylazine hydrochloride and acepromazine maleate    in saline) and the dose is introduced over 20-30 s via a    polyethylene PE-10 tube inserted approximately 5 mm into the nasal    cavity of the rat.

For cynomolgus monkey studies, groups of three male monkeys, typicallyranging in weight between 3.0 and 4.5 kg, were given a single dose ofExample or reference compound via one of the following routes: iv or sc,using doses, dose volumes and vehicles specified in Table 5. Followingdosing by the routes above blood samples were taken at several timepoints (typically pre-dose, 0.083, 0.25, 0.5 1, 2, 4, 8 and 24 h) viaserial tail vein bleeds (rat) or cephalic or saphenous vein (monkey)from the animal and centrifuged to separate plasma for analysis byLC/MS/MS assay. WinNonlin v6.2 statistics software (PharsightCorporation, California, USA) was used to generate pharmacokineticparameters using the non-compartmental model.

TABLE 4 Rat iv pharmacokinetics Dose Dose volume Clearance (mg/kg)(mL/kg) Vehicle (mL/min/kg) olcegepant 5 1 10% DMAC + 10% 18SolutolHS15 + 80% Saline Example 2 2 1 10% DMAC + 10% 7 SolutolHS15 +80% Saline Rat sc pharmacokinetics Dose Dose volume Bioavailability(mg/kg) (mL/kg) Vehicle (%) olcegepant 1 5 10% DMAC + 10%  48%SolutolHS15 + 80% Saline Example 2 1 2 Acidified saline 100% Rat INpharmacokinetics Dose Dose concentration, Bioavailability (mg/kg) Dosevolume Vehicle (%) olcegepant 1.3  6 mg/mL, 50 μL Acidified saline 8Example 2 1 12 mg/mL, 25 μL Acidified saline 20

TABLE 5 Cynomolgus monkey iv pharmacokinetics Dose Dose volume Clearance(mg/kg) (mL/kg) Vehicle (mL/min/kg) Example 2 1 1 Acidified saline 8Cynomolgus monkey sc pharmacokinetics Dose Dose volume Bioavailability(mg/kg) (mL/kg) Vehicle (%) Example 2 0.5 1 Acidified saline 100

Thermodynamic solubility profiling. A 50 mM DMSO stock solution of testcompound was prepared, and from this, a working solution of 1 mM wasprepared by dilution with DMSO. The UV absorbance of working solutionwas scanned from 220 nm to 1000 nm to identify the wavelength maxima oftest compound. The 1 mM working solution was then serially diluted inDMSO to different concentrations to determine linearity/calibrationcurve. To ascertain the aqueous thermodynamic solubility of testcompound, samples were added to a volume of PBS buffer (pH 7.4) orSodium Phosphate Buffer (pH 6.0) which was appropriate to generate afinal concentration of 1 mg/mL if all test compound dissolved. Theresulting solution was then kept on a RotoSpin shaker at 50 rpm for 24 hat rt before the solution was filtered using 0.45 micron PVDF injectorfilters in order to remove the insoluble fraction of the compound.Subsequently, 150 uL of the filtrate is taken for quantification using aUV spectrophotometer, acquiring the optical density of standardsolutions and test compound at the same wavelength maxima. From theoptical density of test compound the thermodynamic solubility iscalculated using the linearity/calibration curve and expressed asmicromolar (μM). Solubility profiles of certain compounds of theinvention are detailed in Table 6.

TABLE 6 Reference Cpd/ Thermodynamic solubility (μM) Example pH 6 pH 7.4olcegepant 150 431 Example 1 1029 Not tested Example 2 1287 800 Example3 1432 1548 Example 4 1346 1148 Example 5 1575 1458 Example 6 1496 1571Example 7 3627 2160

1. A method for treating a cerebrovascular or vascular disorder in asubject comprising administering to the subject a compound of formula(I)

or a salt thereof or an optical isomer thereof, wherein R¹ is

R² is H or forms a spirocyclic heterocyclic ring with R³; R³ forms aspirocyclic heterocyclic ring with R² or is a heterocyclic ring if R² isH.
 2. The method of claim 1, wherein the cerebrovascular or vasculardisorder is migraine without aura, chronic migraine, pure menstrualmigraine, menstrually-related migraine, migraine with aura, familialhemiplegic migraine, sporadic hemiplegic migraine, basilar-typemigraine, cyclical vomiting, abdominal migraine, benign paroxysmalvertigo of childhood, retinal migraine, status migrainosus, clusterheadache, dialysis headache, paroxysmal hemicrania, osteoarthritis, hotflashes associated with menopause or medically induced menopause due tosurgery or drug treatment, hemicrania continua, cyclic vomitingsyndrome, allergic rhinitis, rosacea, dental pain, earache, middle earinflammation, sunburn, joint pain associated with osteoarthritis andrheumatoid arthritis, cancer pain, fibromyalgia, diabetic neuropathy,pain associated with inflammatory bowel disease—Crohn's disease, gout,complex regional pain syndrome, Behçet's disease, endometriosis pain,back pain, or cough.
 3. The method of claim 1, wherein the compound isadministered via a non-oral route.
 4. The method of claim 3, wherein thenon-oral route of administration is an intranasal route, a sub-cutaneousroute or an intravenous route.
 5. The method of claim 1, wherein R¹ is


6. The method of claim 1, wherein R² is H and R³ is


7. The method of claim 6, wherein R³ is


8. The method of claim 1, wherein R² forms a spirocyclic heterocyclicring with R³ to form


9. The method of claim 1, wherein the compound of formula (I) isselected from the group consisting of:N-{(2R)-3-(7-methyl-1H-indazol-5-yl)-1-oxo-1-[8-(piperidin-4-yl)-2,8-diazaspiro[4.5]dec-2-yl]propan-2-yl}-4-(2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridin-1-yl)piperidine-1-carboxamide;N-[(2R)-1-[8-(N-methyl-D-alanyl)-2,8-diazaspiro[4.5]dec-2-yl]-3-(7-methyl-1H-indazol-5-yl)-1-oxopropan-2-yl]-4-(2-oxo-1,2-dihydroquinolin-3-yl)piperidine-1-carboxamide;N-[(2R)-1-[8-(N-methyl-D-alanyl)-2,8-diazaspiro[4.5]dec-2-yl]-3-(7-methyl-1H-indazol-5-yl)-1-oxopropan-2-yl]-4-(2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridin-1-yl)piperidine-1-carboxamide;N-{(2R)-3-(7-methyl-1H-indazol-5-yl)-1-oxo-1-[8-(piperidin-4-yl)-2,8-diazaspiro[4.5]dec-2-yl]propan-2-yl}-4-(2-oxo-1,4-dihydroquinazolin-3(2H)-yl)piperidine-1-carboxamide;N-[(2R)-1-[8-(N-methyl-D-alanyl)-2,8-diazaspiro[4.5]dec-2-yl]-3-(7-methyl-1H-indazol-5-yl)-1-oxopropan-2-yl]-2′-oxo-1′,2′-dihydro-1H-spiro[piperidine-4,4′-pyrido[2,3-d][1,3]oxazine]-1-carboxamide;N-[(2R)-1-[8-(N-methyl-D-alanyl)-2,8-diazaspiro[4.5]dec-2-yl]-3-(7-methyl-1H-indazol-5-yl)-1-oxopropan-2-yl]-4-(2-oxo-1,4-dihydroquinazolin-3(2H)-yl)piperidine-1-carboxamide;andN-{(2R)-3-(7-methyl-1H-indazol-5-yl)-1-oxo-1-[8-(pyridin-4-yl)-2,8-diazaspiro[4.5]dec-2-yl]propan-2-yl}-4-(2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridin-1-yl)piperidine-1-carboxamide;or a salt thereof or an optical isomer thereof.
 10. The method of claim1, wherein the compound of formula (I) is selected from the groupconsisting of:N-{(2R)-3-(7-methyl-1H-indazol-5-yl)-1-oxo-1-[8-(piperidin-4-yl)-2,8-diazaspiro[4.5]dec-2-yl]propan-2-yl}-4-(2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridin-1-yl)piperidine-1-carboxamide;N-[(2R)-1-[8-(N-methyl-D-alanyl)-2,8-diazaspiro[4.5]dec-2-yl]-3-(7-methyl-1H-indazol-5-yl)-1-oxopropan-2-yl]-4-(2-oxo-1,2-dihydroquinolin-3-yl)piperidine-1-carboxamide;N-[(2R)-1-[8-(N-methyl-D-alanyl)-2,8-diazaspiro[4.5]dec-2-yl]-3-(7-methyl-1H-indazol-5-yl)-1-oxopropan-2-yl]-4-(2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridin-1-yl)piperidine-1-carboxamide;N-{(2R)-3-(7-methyl-1H-indazol-5-yl)-1-oxo-1-[8-(piperidin-4-yl)-2,8-diazaspiro[4.5]dec-2-yl]propan-2-yl}-4-(2-oxo-1,4-dihydroquinazolin-3(2H)-yl)piperidine-1-carboxamide;N-[(2R)-1-[8-(N-methyl-D-alanyl)-2,8-diazaspiro[4.5]dec-2-yl]-3-(7-methyl-1H-indazol-5-yl)-1-oxopropan-2-yl]-2′-oxo-1′,2′-dihydro-1H-spiro[piperidine-4,4′-pyrido[2,3-d][1,3]oxazine]-1-carboxamide;N-[(2R)-1-[8-(N-methyl-D-alanyl)-2,8-diazaspiro[4.5]dec-2-yl]-3-(7-methyl-1H-indazol-5-yl)-1-oxopropan-2-yl]-4-(2-oxo-1,4-dihydroquinazolin-3(2H)-yl)piperidine-1-carboxamide;andN-{(2R)-3-(7-methyl-1H-indazol-5-yl)-1-oxo-1-[8-(pyridin-4-yl)-2,8-diazaspiro[45]dec-2-yl]propan-2-yl}-4-(2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridin-1-yl)piperidine-1-carboxamide.11. The method of claim 1, wherein the compound of formula (I) is


12. The method of claim 1, wherein the compound of formula (I) is

or a salt thereof or an optical isomer thereof.
 13. A method ofsynthesizing a compound of formula (I)

or a salt thereof or an optical isomer thereof, wherein R¹ is

R² is H or forms a spirocyclic heterocyclic ring with R³; R³ forms aspirocyclic heterocyclic ring with R² or is a heterocyclic ring if R² isH.